1 Name of Medicine
Budesonide.
Formoterol (eformoterol) fumarate dihydrate (hereafter referred to as formoterol).
2 Qualitative and Quantitative Composition
DuoResp Spiromax is available as a multidose inspiratory flow driven, metered dose dry powder inhaler (Spiromax). To avoid confusion, DuoResp Spiromax is labelled as the metered dose of the corresponding monotherapy products budesonide and formoterol dry powders for inhalation. The monotherapy products are also labelled as metered doses. Table 1 gives the corresponding dose delivered to the patient.
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/SPIROM01.gif Excipient(s) with known effect. Lactose monohydrate.
For full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
White or off-white powder in a multi-dose dry powder inhaler.
4 Clinical Particulars
4.9 Overdose
An overdose of formoterol may lead to effects that are typical for β2-adrenergic agonists: tremor, headache, palpitations, and tachycardia. Monitoring of serum potassium concentrations may be warranted. Hypotension, metabolic acidosis, hypokalaemia and hyperglycaemia may also occur. Supportive and symptomatic treatment may be indicated. β-blockers should be used with care because of the possibility of inducing bronchospasm in sensitive individuals. A metered dose of 120 microgram administered during three hours in patients with acute bronchial obstruction raised no safety concerns.
Acute overdosage with budesonide, even in excessive doses, is not expected to be a clinical problem. However, the plasma cortisol level will decrease and number and percentage of circulating neutrophils will increase. The number and percentage of lymphocytes and eosinophils will decrease concurrently. When used chronically in excessive doses, systemic glucocorticosteroid effects, such as hypercorticism and adrenal suppression, may appear.
Withdrawing budesonide/formoterol or decreasing the dose of budesonide will abolish these effects, although the normalisation of the HPA-axis may be a slow process.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.3 Preclinical Safety Data
Genotoxicity. Individually, budesonide and formoterol were not genotoxic in a series of assays for gene mutations (except for a slight increase in reverse mutation frequency in Salmonella typhimurium at high concentrations of formoterol fumarate), chromosomal damage and DNA repair. The combination of budesonide and formoterol has not been tested in genotoxicity assays.
Carcinogenicity. The carcinogenic potential of the budesonide/formoterol combination has not been investigated in animal studies.
In formoterol carcinogenicity studies performed by AstraZeneca, there was a dose dependent increase in the incidence of uterine leiomyomas in mice dosed orally at 0.1, 0.5 and 2.5 mg/kg/day for two years, and a mesovarian leiomyoma was observed in a female rat dosed by inhalation at 0.13 mg/kg/day for two years. The effects observed are expected findings with high dose exposure to β2-agonists.
Formoterol carcinogenicity studies performed by other companies used systemic exposure levels 800 to 4800-fold higher than those expected upon clinical use of formoterol (based on an 18 microgram daily dose).
Some carcinogenicity activity was observed in rats and mice. However, in view of the dose levels at which these effects were observed and the fact that formoterol is not mutagenic (except for very weak activity at high concentrations in one test system), it is concluded that the cancer risk in patients treated with formoterol fumarate is no greater than for other beta-adrenoceptor agonists.
The carcinogenic potential of budesonide has been evaluated in the mouse and rat at oral doses up to 200 and 50 microgram/kg/day, respectively. In male rats dosed with 10, 25 and 50 microgram budesonide/kg/day, those receiving 25 and 50 microgram/kg/day showed an increased incidence of primary hepatocellular tumours. In a repeat study this effect was observed in a number of steroid groups (budesonide, prednisolone, triamcinolone acetonide) thus indicating a class effect of corticosteroids.
6 Pharmaceutical Particulars
6.7 Physicochemical Properties
Budesonide is a white to off white crystalline powder. It is freely soluble in methylene chloride, sparingly soluble in ethanol and practically insoluble in water.
Formoterol (eformoterol) fumarate dihydrate is a white or almost white or slightly yellow powder. It is slightly soluble in water, soluble in methanol, slightly soluble in 2-propanol and practically insoluble in acetonitrile.
Chemical structure. Budesonide. Budesonide is a non halogenated glucocorticoid structurally related to 16α hydroxyprednisolone. The chemical name is 16α, 17α - 22 R, S-propylmethylenedioxypregna- 1,4-diene-β, 21-diol-3, 20-dione.
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSBDSNDE.gif CAS number. 51333-22-3.
Chemical structure. Formoterol (eformoterol) fumarate dihydrate. (R*R*)-(±)-N-[2-hydroxy-5- [1-hydroxy-2-[[2- (4-methoxyphenyl)-1-methylethyl] amino] ethyl] phenyl] formamide, (E)-2- butendioate (2:1), dihydrate. The chemical structure of formoterol (eformoterol) fumarate dihydrate is:
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSFRMTRL.gif CAS number. 183814-30-4.
7 Medicine Schedule (Poisons Standard)
Prescription only medicine (Schedule 4).
Summary Table of Changes
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/SPIROMST.gif
